Siglecs are members of lg superfamily lectins that recognize sialoside-containing structure. We have recently reported that CD24-Siglec G/10 interaction regulates inflammatory responses to danger-associated (DAMPs) but not pathogen-associated (PAMPs) molecular patterns and proposed this interaction as the foundation for self-nonself discrimination in innate immunity. However, since exposure to PAMPs may also cause release of DAMPs, it is challenging to distinguish septic from aseptic injuries. This paradox is partially reconciled by our recent discovery that sialidases encoded by pathogens disrupt the CD24-Siglec G interaction and exacerbate inflammation. However, this notion only applies to sialidase-producing pathogens. In order to expand the original concept to infections by non-sialidase-producing microbes, we hereby hypothesize that host sialidases are mobilized by PAMPs to disrupt sialoside-based pattern recognition. This hypothesis is supported by our preliminary data that a novel sialidase inhibitor 2,3-dehydro-2-deoxy-N-glycolylneuraminic acid (NeuGC2en) conferred 100% protection against lethal endotoxic shock. Since endotoxin has no microbes-derived sialidase, the inhibitor has to target the host sialidase. Therefore, the first ai of the study is to identify the host sialidase responsible for exacerbating inflammation. In addition, since the inhibitor protects WT, CD24-/- and Siglecg-/- mice equally well, its therapeutic effect must be independent of CD24-Siglec G interaction. Our second aim is therefore to identify the Siglec responsible protection against endotoxic shock. Our proposed studies will not only expand the horizon of sialoside-based pattern recognition in self-nonself discrimination in innate immune response, but also suggest novel therapeutic approaches for endotoxic shock, which is a major unmet medical challenge.